GENETIC STUDIES OF CRANIOFACIAL AND LIMB DISORDERS

颅缝融合是颅缝过早融合的一种常见症状。 导致头部形状异常的发育异常。在中等至 严重者，有颅内压升高和神经症状。 后遗症，如果不手术治疗的话。颅缝早闭是该病的一个特征。 多达50种遗传综合症。肢体畸形，如并指畸形 和短指，是这些情况的共同相关特征。 Crouzon、Jackson-Weiss和Pfeiffer综合征是常染色体显性遗传， 颅缝融合病症的表现有很大的变异性。我们 确定了具有这些条件的家系来研究他们的染色体 和/或已建立的淋巴母细胞或成纤维细胞培养的DNA。 已发现成纤维细胞生长因子受体2(FGFR2)突变 在这种情况下。 我们研究了39例患有这三种情况之一的FGFR2轴突 伊利亚和伊利克突变。在17个无关的基因中检测到11个突变 案子。在之前的轴突Ilia或Axon Lic中有四个突变 仅在Crouzon综合征中报告的病例也出现在其他病例中 两种综合症。两个插入物，一个在Crouzon综合征中的轴突髂骨 一例为Pfeiffer综合征患者，另一例为轴突样变。 观察到的。后来的突变具有相同的替代RNA剪接 作为Crouzon综合征的同义突变的报道。一个 在一家系中检测到错义突变V359F，其中一名成员患有 颅缝融合和宽趾，诊断Pfeiffer综合征，以及 有两个特征与Crouzon综合征一致的成员， 无肢体畸形的颅缝早闭。家庭间和家庭内 FGFR2突变表达的变异性表明这三个 被认为是临床上不同的综合征，而不是 代表了一系列相关的颅脑融合和数字化 精神错乱。 我们还研究了一种罕见的常染色体显性遗传病，其特征是 丘状回皱纹皮肤病，疣状增生性皮肤病 黑棘皮病、颅缝早闭、 颅面畸形、指端畸形、脐带和肛门畸形 异常和早逝。我们检测到FGFR2基因突变 病情，BeareStevenson皮肤回综合征。与综合症不同 如上所述，在轴突中发现了这些突变(Y375C和S372C 10，其包含近端区域或跨膜结构域 它本身。这些突变可能影响所有FGFR2亚型，除了 可溶异构体。Bek(IIIc)和角质形成细胞的生长 FGFR2的KGFR(Illb)亚型因子受体 外显子lilc和lilb的剪接将分别受到影响，因为 这些外显子位于轴突10的上游。Beare-Stevenson的表型 证候与心绞痛的时空表达模式相一致 这两种异构体都是。BEK亚型主要表达为 原始骨和KGFR亚型主要存在于上皮源性 参与皮肤发育的组织。

Craniosynostosis, the premature fusion of calvarial sutures, is a common developmental anomaly that causes abnormal head shape. In moderate to severe cases, there is increase intracranial pressure and neurological sequelae, if not surgically treated. Craniosynostosis is a feature of as many as 50 genetic syndromes. Limb abnormalities, such as syndactyly and brachydactyly, are common associated features of these conditions. Crouzon, Jackson-Weiss, and Pfeiffer syndromes are autosomal dominant, craniosynostotic conditions with a wide variability of expression. We ascertained families with these conditions to study their chromosomes and/or DNA from established lymphoblastoid or fibroblast cell cultures. Fibroblast growth factor receptor 2 (FGFR2) mutations have been found in these conditions. We studied 39 cases with one of these three conditions for FGFR2 axon IlIa and llIc mutations. Eleven mutations were detected in 17 unrelated cases. Four mutations in either axon IlIa or axon llIc previously reported only in Crouzon syndrome are present also in one of the other two syndromes. Two insertions, one in axon IlIa in a Crouzon syndrome patient and the other in axon llIc in a Pfeiffer syndrome patient, were observed. The lafter mutation has the same alternative RNA splicing effect as a reported synonymous mutation for Crouzon syndrome. A missense mutation, V359F, was detected in a family with one member with craniosynostosis and broad digits, diagnostic of Pfeiffer syndrome, and with two member with features consistent with Crouzon syndrome, craniosynostosis without limb anomalies. The inter- and intrafamilial variability in expression of FGFR2 mutations suggests that these three syndromes, presumed to be clinically distinct, are instead representative of a spectrum of related craniosynostotic and digital disorders. We also studied a rare, autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, verrucous hyperplasia with hyperpigmentation of acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities and early death. We detected FGFR2 mutations in this condition, BeareStevenson cutis gyrata syndrome. Unlike the syndromes mentioned above, these mutations (Y375C and S372C) were found in axon 10 which contains the proximal region of or the transmembrane domain itself. These mutations presumably affect all FGFR2 isoforms, except soluble isoforms. Both the BEK (IIIc) and the keratinocyte growth factor receptor, KGFR (Illb) isoforms of FGFR2 formed by alternative splicing of exons lilc and lilb, respectively, would be affected because these exons are upstream of axon 10. The phenotype of Beare-Stevenson syndrome is consistent with the spatiotemporal expression patterns of both of these isoforms. The BEK isoform is expressed primarily in primordial bone and KGFR isoform predominantly in epithelial-derived tissues involved in the development of the skin.